a Synaptic Function Section, The Porter Neuroscience Research Center , National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda , MD , USA.
b Department of Cell Biology and Neuroscience , Rutgers, The State University of New Jersey , Piscataway , NJ , USA.
Autophagy. 2017 Oct 3;13(10):1792-1794. doi: 10.1080/15548627.2017.1356552. Epub 2017 Aug 16.
Chronic mitochondrial dysfunction has been implicated in major neurodegenerative diseases. Long-term cumulative pathological stress leads to axonal accumulation of damaged mitochondria. Therefore, the early removal of defective mitochondria from axons constitutes a critical step of mitochondrial quality control. We recently investigated the axonal mitochondrial response to mild stress in wild-type neurons and chronic mitochondrial defects in amyotrophic lateral sclerosis (ALS)- and Alzheimer disease (AD)-linked neurons. We demonstrated that remobilizing stressed mitochondria is critical for maintaining axonal mitochondrial integrity. The selective release of the mitochondrial anchoring protein SNPH (syntaphilin) from stressed mitochondria enhances their retrograde transport toward the soma before PARK2/Parkin-mediated mitophagy is activated. This SNPH-mediated response is robustly activated during the early disease stages of ALS-linked motor neurons and AD-related cortical neurons. Our study thus reveals a new mechanism for the maintenance of axonal mitochondrial integrity through SNPH-mediated coordination of mitochondrial stress and motility that is independent of mitophagy.
慢性线粒体功能障碍与多种神经退行性疾病有关。长期累积的病理性应激导致轴突中受损线粒体的积累。因此，早期将有缺陷的线粒体从轴突中清除是线粒体质量控制的关键步骤。我们最近研究了野生型神经元中轻度应激下的轴突线粒体反应，以及肌萎缩侧索硬化症 (ALS) 和阿尔茨海默病 (AD) 相关神经元中的慢性线粒体缺陷。我们证明了重新激活应激线粒体对于维持轴突线粒体完整性至关重要。应激线粒体中锚定蛋白 SNPH（syntaphilin）的选择性释放增强了它们向胞体的逆行运输，然后才激活 PARK2/Parkin 介导的线粒体自噬。在 ALS 相关运动神经元和 AD 相关皮质神经元的疾病早期阶段，这种 SNPH 介导的反应被强烈激活。因此，我们的研究揭示了一种新的机制，通过 SNPH 介导的线粒体应激和运动的协调来维持轴突线粒体的完整性，该机制独立于线粒体自噬。
